Shelton first came to mainstream attention when he co-wrote and co-starred in Hamish & Andy (2004) and Real Stories (2006). He was also a co-writer of Chris Lilley's award-winning We Can Be Heroes: Finding The Australian of the Year (2005). In 2007, he became a regular cast member on television programme Rove. His signature segment in 2007 was called Rydeas (pronounced "rye-deers" as in "Ryan's ideas"). In 2008, he started a new segment called Investigationing (a neologism) and, in 2009, introduced a segment called "Philosophisationing".
He was an occasional co-host on the radio show Get This. He also appeared on Red Hot Go, a late night radio show on FOX FM in Melbourne on Monday nights. In December 2007, Shelton presented the Summer Fling breakfast show across the Austereo Today Network with Jules Lund and Tamsyn Lewis. In February 2008, he joined Nova FM to present a Saturday morning breakfast program Ryan & Monty with Katie Dimond. It aired from 10am to 12pm. From January 2009 to 2010, he hosted the Nova FM drive time slot on Ryan, Monty & Wippa between 4-6pm weekdays with Katie Dimond (aka Monty) and Michael "Wippa" Wipfli.
Shelton has also appeared on the improvisational comedy Thank God You're Here as well as Hamish and Andy's Gap Year. Shelton also appeared briefly on the ABC's TwentySomething.
From February 15th to May 24th, 2011, Shelton hosted a comedy podcast entitled Ryan Shelton: For One Minute Only. As the title suggested, Shelton presented comedic skits and absurdist humour within the timeframe of sixty seconds. The podcast ran for fifteen episodes.
To date, Shelton has appeared twice on The Little Dum Dum Club. His first episode was the 21st overall, which was originally posted on March 16th, 2011. In February of 2012, he returned to the program alongside fellow returning guest Peter Helliar for the 70th episode.